1. Field of the Invention
The present invention relates to an agent for curing ischemic myocardial disease comprising an effective amount of diadenosine 5',5"'-p.sup.1,p.sup.4 -tetraphosphate or a pharmaceutically-acceptable salt thereof.
2. Discussion of Background
Angina pectoris and myocardial infarction are diseases that cause heart failure, which occur when coronary blood flow is stopped or considerably reduced as a result of coronary vessel atherosclerosis and thrombosis, triggering an imbalance in oxygen supply to the cardiac muscle. Such diseases are collectively referred to as ischemic myocardial disease.
It is said that at the tame of ischemic myocardial attack, it is extremely important to expand the coronary vessel to sufficiently improve blood flow as quickly as possible.
This is crucial because the longer the ischemic attack, the greaterthe the risk that the impairment to the myocardial function and coronary vessel will become irreversible. To prevent this, vasodilators such as nitroglycerin or thrombolytic agents are used. However, these agents are not always effective and many times their effect is either insufficient or totally irrelevant. In that case, for instance, percutaneous transluminal coronary angioplasty (PTCA) and a coronary bypass operation (grafting of peripheral arteries or venae) are carried out.
Ischemic preconditioning (IP) was first discovered by Murry, C. E., Jennings, R. B. and Reimer, K. A. as reported in "Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium" in Circulation 74, 1124-1136, 1986. Later, ischemic preconditioning using adenosine was conducted by Liu, G. S., Van Winkkle, D. M. et al. as reported in "Protection against infarction afforded by preconditioning is mediated by A.sub.1 adenosine receptors in rabbit heart" in Circulation 84, 350-356, 1991.
The experimental discovery of ischemic preconditioning (IP) revealed that by causing a short (2-5 min.) myocardial ischemia to occur once or several tames prior to a long myocardial ischemia, resistance against the longer attack increases. When IP is conducted, the amount Of endogenous adenosine increases. In view of this, adenosine is considered as an endogenous compound capable of protecting cardiac muscle against ischemia.
In the course of the search for a better cardiac muscle protection against ischemia to replace adenosine, the inventors of the present invention discovered that diadenosine 5',5"'-p.sup.1,p.sup.4 -tetraphosphate was capable of increasing coronary blood flow--even in ischemic states in which adenosine failed--and of exhibiting a myocardial protection effect against ischemia.
These phenomena obviously indicate that diadenosine 5',5"'-p.sup.1,p.sup.4 -tetraphosphate has a myocardial protection mechanism different from that of adenosine.
Diadenosine 5',5"'-p.sup.1,p.sup.4 -tetraphosphate is known to have such bioactivities as an ADP-induced human platelet aggregation inhibitory effect (J. Leuthje and A. Ogiluie, Biochem. Biophys. Res. Commun., 118, 704, 1984), a vasodilating effect on rabbit mesenteric arteries (R. Busse et al. Am. J. Physiol., 254, 828, 1988), an anti-arrhythmia effect (Japanese Laid-Open Patent Application 3-167126), a deliberated hypotensive effect (Japanese Laid-Open Patent Application 5-286861), and a vasodilating effect on coronary vessels at normal time.
However, as for no reports have ever confirmed the possibility that diadenosine 5',5"'-p.sup.1,p.sup.4 -tetraphosphate can be used as an agent for curing ischemic myocardial disease based on the discovery that diadenosine 5',5"'-p.sup.1,p.sup.4 -tetraphosphate is capable of increasing coronary blood flow even in a state of excessive myocardial ischemia and also capable of exhibiting a myocardial protection effect against ischemia.